U.S. Pat. No. 5,145,684 discloses particles of a drug substance having a surface modifier absorbed on the surface thereof and methods for the preparation thereof by wet grinding. These particles have demonstrated significant pharmaceutical utility. Suitable surface modifiers described include various polymers. The surface modifiers disclosed include Pluronic F68 and F108, which are block copolymers of ethylene oxide and propylene oxide; Tetronic 908, which is a tetrafunctional block copolymer derived from sequential addition of propylene oxide and ethylene oxide to ethylene diamine; sodium dodecylsulfate, dialkyl esters of sodium sulfosuccinic acid such as Aerosol OT.TM., sodium lauryl sulfate, and Triton.TM. X-200.
U.S. Pat. No. 5,318,767 discloses X-ray contrast compositions comprising particles of an X-ray contrast agent having a surface modifier absorbed on the surface thereof and methods for the preparation thereof by wet grinding. The above-noted surface modifiers are also disclosed as being useful therein. These X-ray contrast compositions have demonstrated remarkable utility in X-ray medical dianostic imaging procedures.
U.S. Pat. No. 5,340,564 discloses therapeutic and diagnostic compositions with Olin-10 G, i.e., p-isononylphenoxypoly(glyciodol) having improved autoclave stability.
However, sterilization of therapeutic and diagnostic agents in nanoparticulate form stabilized by a surface modifier is difficult. Filtration using a filter of 0.22 .mu.m mesh size is sufficient to remove most bacteria, but the nanoparticles, due to their sizes, cannot be sterile filtered without accounting for substantial drug losses. Conventional autoclaving (steam heat) at 121.degree. C. generally results in substantial increase in particle size, rendering the resulting particles unusable. One possible explanation is that the aggregation of nanoparticles upon heating is related to the phase separation of the surface modifier (surfactant) at or below the sterilization temperature where the bound surfactant molecules are likely to dissociate from the nanoparticles and precipitate, leaving the nanoparticles unprotected. The unprotected nanoparticles can then aggregate into clusters of particles. Upon cooling, the surfactant redissolves into the solution, which then coats the aggregated particles and prevents them from dissociating into smaller ones.
Additional difficulties of some of the above-described surfactants relate to biological usage and wet grinding method.
For example, some of the above-described surfactants have demonstrated less than Superior toxicological profiles such as T908, DOSS, Pluronic S127 and Olin 10G. In addition, these prior art surfactant coatings, when adsorbed to nanoparticles, on some occasions, have exhibited less than desirable uptake of nanoparticles by macrophages.
Moreover, the wet grinding methods described in the patents noted above often entail grinding for days or even weeks which can be undesirable, e.g., from the standpoint of process scale-up.
Consequently, it would be highly desirable to provide surfactant coatings for nanoparticles which provide improved resistance to particle size increase during autoclaving, exhibit improved toxicological profiles, minimize macrophage uptake and facilitate particle size reduction such that milling time can be reduced and/or sterile filtration of the nanoparticles can be accomplished without substantial particle losses.